Background: Comprehensive high throughput functional kinase activity in localized cc-RCC tumors may assist in devising a classification system and help identify potential therapeutic targets. Methods: Patients (pts) with localized tumors undergoing surgery with minimum follow-up of 18 months underwent kinomics of fresh frozen cc-RCC tumors and matched normal renal tissue using the PamStation12 high-content phospho-peptide substrate microarray system (PamGene). The protein tyrosine kinome (PTK) and serine/threonine kinome (STK) PamChips were used to measure global kinase activity. Advanced network modeling of altered phospho-peptides was performed using MetaCore while upstream kinase prediction scoring was based off of phosphonet (phosphonet.ca). Both unsupervised analyses and supervised analyses of kinomics were done guided by tumor recurrence. Kinomics of tumor and matched normal tissue were compared. Results: Of 41 evaluable pts, the median age was 61 and pathologic stage was 1, 2, 3 and 4 in 19, 1, 20 and 1 pts, respectively. Unsupervised clustering analyses of tumor kinomics showed 3 groups: A (N=12), B (N=16), C (N=13). Potential driver kinases implicated were PFTK1, PKG1 and SRC in groups A, B, and C, respectively. Network modeling of these groups identified many Process Mappings including, but not limited to Inflammation pathways (A), translation initiation (B) and immune response and cell adhesion pathways(C). 5 of 9 pts who progressed were classified as Group C, 1 progressor was in Group B, and 3 were in Group A. Supervised analysis showed decreased CDK1, RSK1-4, ERK1-2, PKG2 and AKT2 kinase activity in those who progressed compared to others. 12 tumors showed increased PIM1 and MAPKAPK3, and decreased JNK2 and CDK1 compared to adjacent normal tissue. Conclusions: Comprehensive kinomics of localized cc-RCC was used to classify tumors based on unsupervised clustering, which appeared to confer differential long-term outcomes while supervised analysis also identified potential pathways related to recurrence. Kinases amplified in renal tumors compared to adjacent normal renal tissue were also identified. Significant heterogeneity of kinases was found with no single dominant kinase across all analyses.